In a focal model of brain ischemia in the spontaneously hypertensive rat (SHR), microvascular perfusion, accumulation of inflammatory mediators, and indices of cellular injury have been correlated spatially and temporally by means of multiple label immunohistochemistry in order to study their role in acute stroke. The findings clearly demonstrate that progressive impairment of microcirculation occurs in regions of brain that undergo progressive damage in the early hours of ischemia. Inhibition of tumor necrosis factor-alpha (TNF-alpha) with TNF-binding protein reduces brain infarct volume in middle cerebral artery occlusion (MCAO) models in the rat and mouse. In addition, TNF-binding protein attenuates the progressive impairment of microvascular perfusion that occurs during the early hours of focal brain ischemia. These findings implicate TNF-alpha as a mediator of progressive brain damage during acute stroke. Lipopolysaccharide (LPS) pretreatment has been demonstrated to induce tolerance to focal brain ischemia in the MCAO model in the SHR. TNF binding protein blocks this tolerance implicating TNF-alpha as the mediator. One feature of this form of tolerance is that the degree of microcirculatory perfusion impairment in brain is reduced.